HIV cases continue to rise among men who have sex with men (MSM) with methamphetamine (METH) use contributing. But, we lack understanding of the neural processes underlying MSM's decisions. How might the neural circuitry differ for sexually risky vs. non-sexually risky MSM? How might chronic METH use modify it? We aim to address this gap, using the resulting knowledge to develop novel interventions to reduce risk-taking. Three key neural systems are hypothesized to play a central role in risky decision making: (1) an amygdala- striatal (dopamine-dependent) neural system, which promotes cue-induced habitual behaviors;(2) a prefrontal cortex neural system, which subserves decision-making, executive functioning, and impulse control capacities;and (3) an insular cortex system, which responds to homeostatic and interoceptive signals triggered by states of deprivation, or by exposure to environmental cues that elicit craving. The resulting "urge" may exacerbate the hypersensitivity of the amygdala-striatal system, or weaken the inhibitory function of the prefrontal system. Magnetic Resonance Imaging techniques applied to decisions, often in virtual environments, in conjunction with computational modeling afford an innovative mix of technologies to systematically investigate, in more realistic contexts, the decision-making processes of METH and non-METH using MSM who chronically engage in risky sex. The volume and gray/white matter density of brain areas in the proposed neural circuit will be quantified for each subject from high resolution MRI scans. DTI (diffusion tensor imaging) will be used to map out the connectivity among the target regions. In addition, the fMRI BOLD responses of these regions will be measured when subjects perform both standard decision-making tasks and make risky sexual decisions in a virtual environment. We will compare: (1) sexually risky MSM who use METH, (2) sexually risky MSM who do not use METH, and (3) non-risky MSM. We will sample from Caucasian, African-American, and Latino MSM. The overarching aim of this proposal is to develop a model of the brain systems involved in risky sexual decision-making for MSM and to understand how dysfunctions in those systems may be related to increases in sexually risky decision-making by both METH using and non-METH using MSM. Our main hypotheses are: H1: Sexually risky MSM will show differential functioning in the dopaminergic, habitual system compared to non-sexually risky men: (H1a) they will take longer to acquire negative contingencies to risky behavior (e.g., money loss or shock) and more quickly acquire positive contingencies, and (H1b) show a tendency to overvalue rewards and underweight risks. H2: Sexual risk takers will show greater activation in the insular cortex (and greater craving or urgency) in response to rewarding stimuli and especially sexual stimuli. H3: Sexual risk takers will show dysfunctions in inhibitory control and executive functioning. Our results on gray/white matter density and connectivity will corroborate those differences between groups. H4: METH use will increase risky sexual decision-making and impact each of the three components of the decision-making circuitry. PUBLIC HEALTH RELEVANCE: The proposed research is of high public health significance, as it will elucidate the neural circuitry underlying sexually risky decisions for high risk-groups of men who have sex with men (MSM). This knowledge will provide the foundation for novel intervention strategies to reduce sexual risk taking and the chance of contracting HIV.